The identification of comprising cells and composition of microenvironment, which is the result of many years of work in many research labs across the globe, has made it possible to see just the tip of iceberg.

The dynamic and fluid nature of microenvironment, with its tumor agonistic and antagonistic cells at one end, and its intricate communication with tumor mass, is leaving us with many unanswered questions, both conceptually and functionally. Tumor associated macrophages, tumor associated fibroblasts, B and T regulatory cells, angiogenesis factors and many other cellular, and humeral factors, comprise elements of tumor microenvironment eco-system [1].

Tissue resident macrophages, originating from bone marrow are among the tumor antagonists. However, the most puzzling of all are tissue resident macrophages that originate from the yolk sac of embryo and dispersed in all organs. These cells collaborate with tumor cells and promote their growth and survival. EFEMP1, (EGF containing fibulin-like matrix protein1), which is mutated in forty percent of all solid tumors, and its variant described in glioblastoma multiforme, contribute to stiffening of matrix of microenvironment, thereby decreasing its plasticity or free energy, which could get conveyed to adjacent malignant cells, leading to a more aggressive phenotype [2].

At the heart of the complex components of micro-environment and the cross talks among its comprising cells at one end, and tumor mass at the other end, there lies one simple and fundamental law, namely, the second law of thermodynamics, and its break down in neoplastic transformation [3].

Consequently, network entropy of tumor cells, tumor mass and the adjacent microenvironment increase dramatically [4]. All the molecular and genetic sub compartments extending into micro-RNA and epigenome get modified accordingly to serve the same purpose. The cross talks among the microenvironment elements and tumor mass, as well as the cross talks between the tumor mass and microenvironment follow the same path.

The puzzling collaboration of embryonic yolk sac originated resident tissue macrophages with tumor mass, lead to demise of malignant phenotype, which is characterized by massive paternalization of material genomic imprinting through the demise of host.

Elimination of paternal genomic imprinting is the fundamental goal of embryogenesis. As such, this puzzling collaboration, which is akin to kiss of death, has a deeply seated goal, dating back to initiation of mitosis in early embryogenesis.

Massive increase in cellular and tissue network entropy in a short period of time, could originate in tumor mass or adjacent microenvironment [5]. Regardless of the site of origin, it spreads like a wave to adjacent cells and structures, through numerous potential mechanisms, ranging from micro-RNA to cellular hair ball (Protein-Protein interaction), to genome and epigenome [6]. Our critical task in future is to decipher these changes through single cell and tissue network entropy calculation, based on available mathematical models and modify them by using A.I, and Nano-technology, as described in my previous publications.